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Detection of Chromosome Abnormalities Pre–High-Dose Treatment in Patients Developing Therapy-Related Myelodysplasia and Secondary Acute Myelogenous Leukemia After Treatment for Non-Hodgkin’s Lymphoma

From the Imperial Cancer Research Fund, Department of Medical Oncology, and Department of Hematology, St Bartholomew’s Hospital, London, United Kingdom.

Address reprint requests to Debra M. Lillington, Imperial Cancer Research Fund Medical Oncology Unit, Science Building, St Bartholomew’s Hospital Medical College, Charterhouse Square, London EC1M 6BQ, United Kingdom; email: d.lillington{at}icrf.icnet.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess whether pre–high-dose therapy (HDT)–related factors play a critical role in the development of therapy-related myelodysplasia (tMDS) or secondary acute myelogenous leukemia (sAML).

PATIENTS AND METHODS: Twenty-nine of 230 patients with a primary diagnosis of non-Hodgkin’s lymphoma (NHL) developed tMDS/sAML after HDT comprising cyclophosphamide and total-body irradiation (TBI) supported by autologous hematopoietic progenitor cells. G-banding and fluorescence in-situ hybridization (FISH) were used to detect clonal cytogenetic abnormalities.

RESULTS: The majority of patients showed complex karyotypes at diagnosis of tMDS/sAML containing, in particular, complete or partial loss of chromosomes 5 and/or 7. Using single locus–specific FISH probes, significant levels of clonally abnormal cells were found before HDT in 20 of 20 tMDS/sAML patients screened, compared with three of 24 patients screened who currently have not developed tMDS/sAML, at a median follow-up of 5.9 years after HDT.

CONCLUSION: Prior cytotoxic therapy may play an important etiologic role and may predispose to the development of tMDS/sAML. Using a triple FISH assay designed to detect loss of chromosomal material from 5q31, 7q22, or 13q14, significant levels of abnormal cells can be detected before HDT and may predict which patients are at increased risk of developing secondary disease. Further prospective evaluation of this FISH assay is warranted to determine its predictive power in this setting.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THERAPY-RELATED myelodysplasia (tMDS) and secondary acute myelogenous leukemia (sAML) are well-recognized late complications of high-dose therapy (HDT) for lymphoid malignancies.^1-8 In patients with non-Hodgkin’s lymphoma (NHL), the incidence of tMDS/sAML after high-dose therapy (HDT) is between 5% and 15%. Should more intensive therapy genuinely prolong survival for a large proportion of patients, there may be an even higher incidence of secondary disease.

Two classes of cytotoxic drugs are known to be associated with the development of tMDS/sAML and with distinctly different cytogenetic profiles. The alkylating agent–related leukemias typically exhibit abnormalities of chromosomes 5 and/or 7, whereas those occurring after exposure to topoisomerase II inhibitors are frequently associated with abnormalities of 11q23 involving the MLL gene.^9-14 Other factors attributed to the development of tMDS/sAML include older age,^7,15,16 total-body irradiation (TBI),^4,17,18 number of hematopoietic stem cells infused, chemotherapy priming of peripheral-blood stem cells^5,15,16,19 and increased interval from diagnosis to HDT,^3,20 although the latter may merely reflect larger cumulative doses of pre-HDT chemotherapeutic agents. The results from the group in Copenhagen²¹ support a dose-response effect of prior alkylating agent therapy with increased risk of developing tMDS/sAML, because multitreated patients with either Hodgkin’s disease or NHL showed a 24.3% risk of secondary leukemia at 43 months. Furthermore, a study from Newcastle²² showed only a 1.1% risk of developing tMDS/sAML at 20 months in patients undergoing transplantation early in the course of their disease.

To address whether pre-HDT factors were significant in the development of tMDS, Abruzzese et al²³ used fluorescence in situ hybridization (FISH) to look for cytogenetic abnormalities in pretransplantation bone marrow samples. In nine of 12 cases studied, abnormal cells were seen pretransplantation, and surprisingly, some cases showed high levels of aberrant cells.

Cytogenetic analysis of tMDS/sAML karyotypes often shows complex aberrations that cannot be fully resolved on G-banding. The majority of patients at St Bartholomew’sHospital (SBH) showed complex karyotypes with frequent loss of material from chromosomes 5 and/or 7, and although prior treatment was heterogeneous, all patients had received alkylating agents.⁷ To determine whether pretransplantation or transplantation-related factors play the critical role in the development of secondary disease, single-copy FISH probes were used to screen 20 of 29 patient samples for evidence of tMDS/sAML clones before HDT. In addition, a further 24 patients who had undergone HDT but who have not developed tMDS/sAML were also screened.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Patients with tMDS/sAML were identified from a cohort of 230 patients with NHL who had received cyclophosphamide and TBI with autologous hematopoietic progenitor-cell support as consolidation of remission between January 1985 and November 1996.^1,7,24,25 The median time from HDT to tMDS/sAML was 4.4 years in the 29 patients. Diagnosis of MDS was made according to French-American-British criteria,²⁶ and only confirmed cases were included in this study. The clinical details of these patients have been described in an earlier publication.⁷

Cytogenetic Analysis
Cytogenetic analysis was performed on short-term bone marrow cultures from 26 of 29 patients at diagnosis of tMDS/sAML using standard G-banding techniques.²⁷ Karyotypes were described according to the International System for Cytogenetic Nomenclature.²⁸ The karyotypes of 24 of these patients have been reported previously.⁷ Fifteen of the 29 patients also had cytogenetic analysis performed pre-HDT, and no abnormal clone was detected in 30 metaphases fully analyzed per patient.

Pre-HDT/At-Collection Cryopreserved Samples
Bone marrow samples taken pre-HDT or at the time of collection, which had been cryopreserved in DMSO and stored in liquid nitrogen, were thawed quickly and washed twice in Gibco RPMI 1640 medium (Gibco BRL, Life Technologies, Paisley, Scotland) with glutamax, supplemented with fetal calf serum (10%) plus penicillin and streptomycin. The cells were then centrifuged at 1,000 rpm for 10 minutes and resuspended in 5 mL of KCl at 37°C for 15 minutes. Cells were centrifuged at 1,000 rpm for 10 minutes and then fixed using 3:1 methanol/acetic acid. Cells were then recentrifuged and fresh fix added before being dropped onto glass slides using standard cytogenetic methods.

FISH
Using the G-banded data and subsequent M-FISH results on 12 of these tMDS/sAML patients (data not shown), informative probes were selected from the stemline (primary) clones and tested on the patient cells at diagnosis of tMDS/sAML. At least one probe was identified as being informative for the tMDS/sAML abnormalities in all patients studied, and in most patients, at least two probes were available. These informative probes were then applied to pre-HDT/at-collection interphase cells from 20 patients using standard techniques. Two hundred interphases per patient were screened where possible and the number of abnormal cells in this population assessed. All slides were independently assessed by two observers and the mean value per 200 cells reported. All abnormal cells detected were visualized using the appropriate single-band pass fluorescence filters and different focal planes viewed to ensure utmost accuracy. Bone marrow aspirates taken at diagnosis of NHL were also screened in three patients as additional patient-specific controls. All probes were tested on five different normal controls to ascertain the levels of false positivity for each probe. Six patients (patients no. 2, 4, 7, 8, 14, and 26) who showed significant levels of abnormal cells pre-HDT were also screened post-HDT for evidence of clonal expansion before morphologic diagnosis of tMDS/sAML.

Statistical Analysis
FISH probes were tested on five different normal control samples (peripheral blood and bone marrow from individuals with no evidence of a hematologic malignancy). Two hundred interphase cells were scored per probe from each of five separate hybridization experiments. The mean cutoff level for a false-positive result was determined per 200 cells and the SD calculated. The number of abnormal cells was determined to be significant when the number exceeded the mean plus three SDs. The results were also analyzed using the binomial distribution, taking the binomial (mean) as the cutoff point (data not shown).

Triple FISH Assay
A triple FISH assay was developed using the three most informative markers for the entire patient group, 5q31 (D5S721/D5S23, Vysis Inc, Downers Grove, IL), 7q22 (H[lowen]DJ0138M12/H[lowen]NH0132A01, kindly provided by Prof S. Scherer, Toronto, Ontario, Canada) and 13q14 (RB1, Vysis Inc). The 5q31 probe was labeled with spectrum orange and included a probe mapping to 5p15.2 labeled with spectrum green acting as an internal control. Cells showing loss of the orange signal (loss of 5q31) were scored as well as cells showing loss of an orange and green signal (monosomy 5). Two probes mapping to 7q22 but labeled with different fluorochromes were applied as a cocktail for greater accuracy, and only cells showing loss of both a red and green signal for the 7q22 locus were scored as abnormal. The RB1 probe was a single locus probe and was directly labeled with spectrum orange. The triple FISH assay was applied to bone marrow taken at collection from one patient (patient no. 17) in whom no cytogenetic analysis was performed at diagnosis of tMDS/sAML and a further 24 patients who had undergone HDT but have not developed tMDS/sAML.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
G-banded analysis at diagnosis of tMDS/sAML was performed in 26 of 29 patients ( Table 1); 24 of these karyotypes have been reported previously.⁷ Twelve of these patients also had retrospective M-FISH analysis performed and the information derived from this has been included in the karyotypes (Table 1). Various single-copy probes were tested on each available tMDS/sAML sample to ensure that they were informative for a particular patient. The following probes represented useful markers for tMDS/sAML clones: alpha-satellite probes for chromosomes 6, 7, 8, 9, and 12, unique sequence probes D5S721/D5S23 (5p15.2/5q31) (Vysis Inc), RB1 (13q14) (Vysis Inc), TEL/AML1 (12p13/21q22) (Vysis Inc), H_DJ0138M12/H_NH0132A01 (7q22/7q22) (kindly provided by Prof Scherer). Figure 1 shows the results from four tMDS/sAML samples using a selection of informative probes. The importance of testing the FISH probes on the tMDS/sAML samples was demonstrated in patient no. 20 who on G-banded analysis showed a deletion of chromosome 5 and loss of chromosome 7. Figure 2 clearly demonstrates a small marker containing alpha-satellite material from chromosome 7 and an insertion of 5q31 into another abnormal chromosome in metaphases from patient no. 20. Neither probes, therefore, are suitable for retrospective screening of tMDS/sAML cells in this patient, although the 7q22 probe cocktail did prove informative. The informative probes were also tested on normal control individuals ( Table 2, Fig 3) to ascertain the cutoff levels for false positivity.

View larger version (25K): [in this window] [in a new window]   Fig 1. FISH analysis on tMDS/sAML samples. Patient no. 14 shows loss of 5p15.2 and 5q31; patient no. 18 shows two clones, trisomy 8 (green) and monosomy 7 (red); patient no. 21 has multiple AML1 (red) signals; patient 27 shows loss of 5q31 (red).

View larger version (12K): [in this window] [in a new window]   Fig 2. FISH analysis (patient no. 20). Upper image shows a normal chromosome 5 with red and green signal, a deleted chromosome 5 containing only the green signal from 5p15.2, and another abnormal chromosome with 5q31 (red signal) inserted. The lower image demonstrates a tiny marker chromosome containing alpha-satellite material from chromosome 7, in addition to a normal chromosome 7.

View larger version (17K): [in this window] [in a new window]   Fig 3. The triple FISH assay shown on normal control cells. The images are as follows: (upper) 5p/5q probe; (middle) 7q22 probes; (lower) RB1 probe.

In the subgroup of 24 patients screened after HDT but without evidence of tMDS/sAML, three patients showed statistically significant numbers of abnormal cells pretransplantation. The clinical characteristics of this group of patients compared with those who developed tMDS/sAML are listed in Table 5. Of the three patients with abnormal cells detected pre-HDT but without morphologic evidence of MDS, one patient showed 47% of cells with loss of an RB1 allele and died of recurrent lymphoma 22 months post-BMT. The last bone marrow aspirate from the latter patient showed mild dyserythropoiesis, and the possibility that the del(13q) was part of the lymphoma clone was excluded because G-banded analysis was performed at the time of lymphoma diagnosis. The other two patients showed 5q-/13q- and 5q-/-7q22, respectively, and in one of these patients, these abnormalities were excluded at diagnosis of lymphoma. In fact, an additional copy of 5p15.2 was seen in 43% of cells and two copies of RB1 in all cells at lymphoma diagnosis compared with loss of one copy of 5q and loss of one RB1 homolog in 3.5% and 7.5% of cells, respectively, pre-HDT. Both the latter two patients are currently alive and well.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Recently, it has been shown by FISH that nine of 12 patients with Hodgkin’s disease, NHL, breast cancer, or multiple myeloma had MDS-related abnormalities present before HDT.²³ The proportion of abnormal cells detected pre-HDT in the latter study was high, ranging from 5% to 46% of cells, with a median value of 25%. The time from HDT to tMDS ranged from 10 to 60 months (median, 38 months); the patient developing tMDS with shortest latency (10 months) had the lowest level of abnormal cells pre-HDT (not statistically significant compared with controls), whereas the patient with 46% of abnormal cells pretransplantation developed tMDS 57 months after HDT. In two patients, the FISH probes used were informative only for evolved sideline abnormalities, ie, did not represent the initial cytogenetic events. No abnormal clones were detected by G-banded analysis in the four patients studied pretransplantation, despite one patient showing 27% abnormal cells by FISH, although this may reflect the lower sensitivity of routine G-banding.

FISH analysis provides a more accurate assessment of the entire population of cells in a given sample because both interphase and metaphase cells can be assessed. In the current study, cryopreserved samples were directly harvested without culturing to ensure no in vitro proliferative selection. FISH also has advantages over G-banding in terms of the speed and ability to score many more cells. Pre-HDT cytogenetic analysis involved the full analysis of 30 metaphase cells per patient, whereas FISH enabled 200 interphase cells to be scored. It was not surprising therefore that FISH analysis revealed low-level abnormal clones in patients with normal G-banded cytogenetic results pre-HDT. The number of clonally abnormal cells seen by FISH in the current study was substantially lower than the levels reported by Abruzzese et al²³ and may account for the longer interval in our series from HDT to the development of tMDS/sAML (median, 53 months compared with 38 months). Abnormal cells were also visualized through single-band pass filters and through different focal planes to ensure greater accuracy in the detection of signals. There was consistency between both observers (SBH) in assessing the number of abnormal cells. The majority of patients screened pre-HDT displayed low-level clones that were nevertheless significantly different from expected levels for normal controls. These results are in keeping with the hypothesis that cytotoxic therapy before HDT plays an important role in the etiology of tMDS/sAML.

In the majority of patients, the clonal abnormalities seen at the time of tMDS/sAML included complete or partial loss of chromosomes 5 and/or 7, which are typically associated with prior alkylating agent therapy, even in the absence of HDT.⁵ The possibility, therefore, that prior cytotoxic therapy may predispose to the development of tMDS/sAML after HDT is critical to the management of future patients being considered for HDT. The contribution of TBI to the development of tMDS/sAML cannot be excluded, and this conditioning regimen may even promote the growth of abnormal cells in some way, because in patients with follicular lymphoma who have not received HDT, the incidence of tMDS/sAML is quite low.^33,34

The majority of patients in this study (25 of 27 with data available) had clonal abnormalities that could be detected using a panel of three FISH probes mapping to 5q31, 7q22, and 13q14. These FISH probes were highly informative for this cohort of patients, and even in the absence of karyotype data at diagnosis of tMDS/sAML (patient no. 17), abnormal cells containing loss of material from chromosome 7 were found pre-HDT. Thus the triple FISH assay has the ability to identify the presence of abnormal cells in this retrospective cohort of patients. In light of these findings, the triple FISH assay could be incorporated into clinical trials to allow evaluation in a prospective fashion, enabling the predictive value of this test to be thoroughly assessed. It would also be interesting to assess bone marrow samples from NHL patients with similar prior therapy but who did not proceed to HDT to ascertain the importance of the HDT itself.

Patient no. 3 had no informative FISH markers available and this patient also had prostate cancer. The pattern of abnormalities seen in patient no. 3 did not fit with those seen in the other patients and perhaps were more consistent with prostate cancer than tMDS/sAML. Patient no. 3 remains alive more than 9 years post-HDT. It was not possible to screen patient no. 29 either, because the interstitial deletion of chromosome 7 seen in this patient at the time of tMDS was more distal to both the 7q22 probe and the 7q31 probe available commercially.

The additional 24 HDT patients screened using the triple FISH assay were selected on the basis that they had received HDT at similar times to the group of patients who did develop tMDS/sAML. The median number of therapies pre-HDT in both groups was three, and the median age was 48 years in the group who developed tMDS/sAML compared with 43 years in the group who did not. The median time from HDT to development of tMDS/sAML was 4.5 years for the former group, compared with a median follow-up of 5.9 years for the latter group. Other clinical features (Table 5) were similar between the two groups.

In light of the incidence of tMDS/sAML in this cohort of patients, the HDT regimen for NHL at SBH was changed in December 1996 from cyclophosphamide and TBI to carmustine, etoposide, cytarabine, and melphalan. Since that time, no patient has developed tMDS/sAML, although follow-up is short (median, 2.4 years).

Treatment of tMDS/sAML is, at present, unsuccessful, with most patients surviving less than 2 years.^18,35 In this series, the median survival from diagnosis of tMDS/sAML was 10 months. Recently, Yakoub-Agha et al³⁶ demonstrated superior survival after allogeneic bone marrow transplantation in patients younger than 38 years with tMDS/sAML, highlighting its importance as a treatment option in this subgroup of patients. Strategies to reduce the development of tMDS/sAML are, however, needed. Using a triple FISH assay, it is feasible to screen patients who have had extensive cytotoxic therapy prospectively to look for evidence of those cytogenetic abnormalities commonly associated with tMDS/sAML. In the current study, only patients who had cyclophosphamide and TBI were assessed, and it is possible that this conditioning treatment compounds the risk of developing tMDS/sAML. Further evaluation of the triple FISH assay in current trials of HDT will be beneficial in predicting its ability to identify those patients who may be at risk.

In summary, the incorporation of this triple FISH assay into clinical trials using HDT is warranted to determine whether patients who are predisposed to developing tMDS/sAML as a consequence of previous cytotoxic therapy can be identified prospectively.

	ACKNOWLEDGMENTS

 
We thank Michael Bradburn and Dr John Radford for valuable discussions and comments on this manuscript. We are grateful also to Nick Telford for providing fixed material from patient no. 23 and Prof Steve Scherer for kindly supplying the 7q22 FISH probes. The analysis for patient no. 26 was performed by Elizabeth Wilkinson as part of a project while studying for a bachelor of medicine degree.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Rohatiner AZ, Johnson PW, Price CG, et al: Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol 12: 1177-1184, 1994[Abstract/Free Full Text]

2. Marolleau JP, Brice P, Morel P, et al: Secondary acute myeloid leukemia after autologous bone marrow transplantation for malignant lymphomas. J Clin Oncol 11: 590-591, 1993 (letter)[Free Full Text]

3. Stone RM, Neuberg D, Soiffer R, et al: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 12: 2535-2542, 1994[Abstract/Free Full Text]

4. Darrington DL, Vose JM, Anderson JR, et al: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12: 2527-2534, 1994[Abstract/Free Full Text]

5. Miller JS, Arthur DC, Litz CE, et al: Myelodysplastic syndrome after autologous bone marrow transplantation: An additional late complication of curative cancer therapy [see comments]. Blood 83: 3780-3786, 1994[Abstract/Free Full Text]

6. Traweek ST, Slovak ML, Nademanee AP, et al: Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin’s disease and non-Hodgkin’s lymphoma. Blood 84: 957-963, 1994[Abstract/Free Full Text]

7. Micallef INM, Lillington DM, Apostolidis J, et al: Therapy-related myelodysplasia (tMDS) and secondary acute myelogenous leukemia (sAML) following High-dose Therapy (HDT) with autologous hematopoietic progenitor cell support for lymphoid malignancies. J Clin Oncol 18: 947-955, 2000[Abstract/Free Full Text]

8. Pedersen-Bjergaard J, Andersen MK, Christiansen DH: Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation. Blood 95: 3273-3279, 2000[Abstract/Free Full Text]

9. Kantarjian HM, Keating MJ, Walters RS, et al: Therapy-related leukemia and myelodysplastic syndrome: Clinical, cytogenetic, and prognostic features. J Clin Oncol 4: 1748-1757, 1986[Abstract]

10. Kaldor JM, Day NE, Clarke A, et al: Leukemia following Hodgkin’s disease. N Engl J Med 322: 7-13, 1990[Abstract]

11. Karp JE, Smith MA: The molecular pathogenesis of treatment-induced (secondary) leukemias: foundations for treatment and prevention. Semin Oncol 24: 103-113, 1997[Medline]

12. Felix CA: Secondary leukemias induced by topoisomerase-targeted drugs. Biochim Biophys Acta 1400: 233-255, 1998[Medline]

13. Pedersen-Bjergaard J, Andersen MK: Secondary or therapy-related MDS and AML and their chromosome aberrations: Important to study but difficult to establish causality. Haematologica 83: 481-482, 1998 (editorial)[Free Full Text]

14. Pedersen-Bjergaard J, Andersen MK, Johansson B: Balanced chromosome aberrations in leukemias following chemotherapy with DNA-topoisomerase II inhibitors. J Clin Oncol 16: 1897-1898, 1998[Medline]

15. Bhatia S, Ramsay NK, Steinbuch M, et al: Malignant neoplasms following bone marrow transplantation. Blood 87: 3633-3639, 1996[Abstract/Free Full Text]

16. Andre M, Henry-Amar M, Blaise D, et al: Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin’s disease. Blood 92: 1933-1940, 1998[Abstract/Free Full Text]

17. Stone R: Myelodysplasic syndrome after autologous transplantation for lymphoma: The price of progress? Blood 83: 3437-3440, 1994[Free Full Text]

18. Friedberg JW, Neuberg D, Stone RM, et al: Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 17: 3128-3135, 1999[Abstract/Free Full Text]

19. Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: An assessment of risk factors. Blood 95: 1588-1593, 2000[Abstract/Free Full Text]

20. Milligan DW, Ruiz de Elvira C, Goldstone AH: Secondary leukemia and myelodysplasia after autografting for lymphoma: Results from the EBMT. Blood 92: 493, 1998 (abstr)

21. Pedersen-Bjergaard J, Pedersen M, Myhre J, et al: High risk of therapy-related leukemia after BEAM chemotherapy and autologous stem cell transplantation for previously treated lymphomas is mainly related to primary chemotherapy and not to the BEAM-transplantation procedure. Leukemia 11: 1654-1660, 1997[Medline]

22. Taylor PRA, Jackson GH, Lennard AL, et al: Low incidence of myelodysplastic syndrome following transplantation using autologous non-cryopreserved bone marrow. Leukemia 11: 1650-1653, 1997[Medline]

23. Abruzzese E, Radford JE, Miller JS, et al: Detection of abnormal pretransplant clones in progenitor cells of patients who developed myelodysplasia after autologous transplantation. Blood 94: 1814-1819, 1999[Abstract/Free Full Text]

24. Foran JM, Apostolidis J, Papamichael D, et al: High-dose therapy with autologous haematopoietic support in patients with transformed follicular lymphoma: A study of 27 patients from a single centre [see comments]. Ann Oncol 9: 865-869, 1998[Abstract/Free Full Text]

25. Apostolidis J, Gupta RK, Grenzelias D, et al: High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up. J Clin Oncol 18: 527-536, 2000[Abstract/Free Full Text]

26. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Hematol 51: 189-199, 1982[Medline]

27. Rooney D, Czepulkdowski B: Human Cytogenetics: A Practical Approach— Vol. II. Malignancy and Acquired Abnormalities (ed 2 ). New York NY, Oxford University Press, 1992

28. Mitelman F: An international system for human cytogenetic nomenclature. Basel Switzerland, Karger, 1995

29. Govindarajan R, Jagannath S, Flick JT: Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br J Haematol 95: 349-353, 1996[Medline]

30. Ketterer N, Salles G, Dumontet C: Fludarabine may increase the toxicity of peripheral blood progenitor cell transplantation. Br J Haematol 102: 204, 1998 (abstr)

31. Harrison CN, Gregory W, Hudson GV, et al: High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin’s disease is unlikely to be associated with a major risk of secondary MDS/AML. Br J Cancer 81: 476-483, 1999[Medline]

32. Wheeler C, Khurshid A, Ibrahim J, et al: Low incidence of post-transplant myelodysplasia/acute leukemia (MDS/AML) in NHL patients autotransplanted after cyclophosphamide, carmustine and etoposide (CBV). Blood 90: 385, 1997 (abstr)

33. Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4: 1470-1480, 1986[Abstract/Free Full Text]

34. Johnson PW, Rohatiner AZ, Whelan JS, et al: Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol 13: 140-147, 1995[Abstract/Free Full Text]

35. Estey EH: Prognosis and therapy of secondary myelodysplastic syndromes. Haematologica 83: 543-549, 1998[Abstract/Free Full Text]

36. Yakoub-Agha I, de La Salmoniere P, Ribaud P, et al: Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: A long-term study of 70 patients—Report of the French Society of Bone Marrow Transplantation. J Clin Oncol 18: 963-971, 2000[Abstract/Free Full Text]

Submitted August 7, 2000; accepted February 6, 2001.

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				C. Metayer, R. E. Curtis, J. Vose, K. A. Sobocinski, M. M. Horowitz, S. Bhatia, J. W. Fay, C. O. Freytes, S. C. Goldstein, R. H. Herzig, et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study Blood, March 1, 2003; 101(5): 2015 - 2023. [Abstract] [Full Text] [PDF]

				M. Hunault-Berger, N. Ifrah, and P. Solal-Celigny Intensive therapies in follicular non-Hodgkin lymphomas Blood, July 30, 2002; 100(4): 1141 - 1152. [Full Text] [PDF]

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